How cancer survivors are teaching researchers — even decades later

Tracking survivors long after treatment ends helps inform medical decisions for today’s patients and much more
Dr. Paul Martin
Dr. Paul Martin is former director of Fred Hutch's Long-term Follow-up Program for bone marrow transplant survivors. Photo by Robert Hood / Fred Hutch News Service

[Editor's note: We've updated this story, originally published in January 2017, to reflect that findings from one of the studies were recently published in the Journal of Clinical Oncology.]

For many years of his career, Dr. Paul Martin had a standing annual tradition. In the days leading up to the New Year’s, he’d sit down and pore over a thick stack of comments from his patients.

As former director of Fred Hutchinson Cancer Research Center’s Long-term Follow-up Program, or LTFU for short, Martin oversaw the team that tracks and follows every patient who’s received a bone marrow transplant through the Hutch. Some of the survivors — who number in the thousands — are 40 or more years out from their transplant at this point.

Every year since its inception in the early 1980s, the program sends out a detailed questionnaire to every transplant survivor. The answers to these questions inform a host of research topics on the long-term effects of transplantation, from graft-vs.-host disease to cataracts, from secondary cancers to infertility and sexual dysfunction.

When Martin became the program’s director in 1999, he added a question to the end of the questionnaire, asking simply whether there was anything else the survivors thought the physician-scientists and other clinicians should know about their experience.

There was a lot, it turned out. So much that Martin needed to take several days over the winter holidays to read through each year’s worth of comments.

“It’s a ton of work. It’s very emotional. I just remember being completely drained after reading them all,” said Martin, who stepped down as program director in 2014 but continues his survivorship research at the Hutch. “There’s incredible joy in some comments and incredible pain in others.”

Dr. Stephanie Lee
Dr. Stephanie Lee Photo by Bo Jungmayer / Fred Hutch News Service

Welcome to the world of long-term follow-up, where dedicated researchers sift through the many possible after effects of potentially toxic cancer therapies. Scientists in this field are the ones who will be following today’s cutting-edge cancer treatments for decades in the future to understand the full scope of their benefits and drawbacks.

Work like theirs doesn’t usually grab the headlines the way the development of new cancer therapies does, said Fred Hutch transplantation researcher Dr. Stephanie Lee, who’s headed the LTFU Program since 2014. But it’s incredibly important.

“It’s human nature to celebrate the cures,” Lee said. “This other work, in terms of survivorship and late effects, is like, now you’ve gotten rid of it, but what are you left with after the treatment?”

Comments sent in on the questionnaires have spurred several changes at the Hutch, from sorting out billing issues the clinicians didn’t realize their patients were experiencing to spurring new research projects on survivorship issues such as sexual after-effects and post-traumatic stress disorder.

But perhaps equally importantly, the comments also have influenced how Martin and his colleagues view the very nature of their jobs — caring for and looking for more insight into this special class of cancer survivors. Some Hutch transplant physicians will even suggest that their patients who are facing transplants should read some of the collections (representative comments are published anonymously on the program website) to get a sense of what to expect.

For LTFU clinicians and staff, reading the collection “is very instructive, because it speaks in the patient’s voice and makes it concrete,” Martin said. “It’s very, very powerful.”

Dr. Mazyar Shadman
Dr. Mazyar Shadman Photo by Robert Hood / Fred Hutch News Service

Balancing risk and benefit

Long-term follow-up is not just for transplant survivors. Many cancer therapies are tracked for years or decades after patients receive treatment. For some, like immunotherapy and other therapies that involve genetically modified cells, the U.S. Food and Drug Administration strongly recommends a 15-year follow-up period to understand the new therapies’ possible delayed effects, Martin said.

Long-term tracking studies are necessary to understand whether a cure is really a cure. When bone marrow transplantation was first developed at the Hutch in the 1960s and ‘70s, it took several years of tracking survivors for researchers to understand that the procedure was working to cure leukemia.

And sometimes, following patients who were treated with older therapies lays the groundwork for a better understanding of new treatments, too. Fred Hutch clinical researcher Dr. Mazyar Shadman led a study published earlier this week in the Journal of Clinical Oncology, describing 10 years of follow-up data from a large clinical trial for patients with follicular lymphoma.

Known as SWOG S0016, the trial was led by former Fred Hutch lymphoma researcher, the late Dr. Oliver Press, who holds the David and Patricia Giuliani/Oliver Press Endowed Chair in Cancer Research. The trial started in 2001 and included more than 500 patients with previously untreated, advanced follicular lymphoma. SWOG S0016 compared a standard combination of chemotherapy drugs commonly referred to by the acronym CHOP, combined with either the immunotherapy drug rituximab, a lymphoma-specific antibody, or a similar antibody-bearing a radioactive molecule. R-CHOP, as the combination of the chemotherapies and rituximab is called, had newly become the standard of care at the time, although it’s not used as frequently these days.

This blood cancer is generally very slow-growing, Shadman said, making lengthy tracking of follicular lymphoma treatments especially important. The study’s initial results, published in 2013, found that both groups of patients — those who’d received rituximab and those who had received the radioimmunotherapy — did very well, with no significant difference in overall survival. Approximately 90 percent of patients were still alive five years after treatment.

Now, after having followed the patients for 10 years, the longer-term results aren’t turning any of those older findings on their head, Shadman said. The two groups continue to do well — about 80 percent of the trial participants were still alive in 2016. Those who’d received rituximab had a slightly higher chance of their cancer coming back as compared to those treated with the radiolabeled antibody, but that didn’t affect their overall survival, the researchers found.

Multiple levels of reassurance

Shadman, who also treats patients with lymphoma and other blood disorders at Seattle Cancer Care Alliance, Fred Hutch’s clinical care partner, finds multiple levels of reassurance from tracking this study for so long. For one, he now can tell his patients exactly what they can expect in terms of their chances for long-term survival if they are treated with the type of combination therapy studied in SWOG S0016, more broadly known as chemoimmunotherapy.

But the follow-up is important not just for patients treated exactly like those in the study, he said. The findings will also be useful as a baseline for comparison. There are a lot of new targeted therapies for follicular lymphoma on the scene or coming down the pike, drugs such as lenalidomide, venetoclax, ibrutinib, and idelalisib, all of which either boost the immune system to act against cancer cells or target specific proteins involved in some follicular lymphomas and other blood cancers.

Researchers and patients alike are excited about the potential of these drugs to improve cancer treatment, but studies like Shadman’s are necessary to provide the context, he said.

“It’s very important to know what are your historical data, what’s your benchmark,” he said. “If you don’t know how well you can do with chemoimmunotherapy, you don’t know if there’s any room for improvement.”

Likewise, similar studies will be needed for those new therapies themselves.

“If I have a new drug today and I give it to my patients and their lymphoma goes away, but I’ve only followed them for six months, what do I know about the risk of other types of cancers five years from now? What if their lymphoma comes back? How difficult is it going to be to treat? These are real issues,” Shadman said. “In medicine, there should be an ongoing assessment of risk and benefit. If you don’t know your long-term risks, you don’t know how reasonable it is to accept that short-term benefit.”

Lymphoma survivor Klev Schoening
Lymphoma survivor Klev Schoening Photo courtesy of Klev Schoening

‘A lot of life that happens’

As much work as it takes to track patients for decades after their treatment, the research can get even more complicated when scientists are trying to sift out potential side effects of cancer therapies years later, Lee said.

“Our population is really complicated because they’ve had all kinds of diseases and all sorts of treatments,” she said. “If you’re talking about a complication that tends to happen 10 or more years afterward, there’s a lot of life that happens after the transplant and before that complication happens. That can also make it challenging to conduct research in this population.”

Klev Schoening, a 59-year-old follicular lymphoma survivor who was diagnosed in 2002 and treated by Press as part of the SWOG S0016 trial, had to develop a new set of expectations for himself after his treatment. An avid mountaineer, he found his physical endurance had taken a hit. But he tries not to dwell on what might have been, he said.

“You get a new normal after your body’s been whacked like that … Everything is relative from that point forward,” Schoening said. “You think you can attribute it to [the treatments], but you don’t know. You’re aging at the same time. There’s no point pondering it; it just is what it is.”

‘If you don’t look, you won’t find it’

Sifting out normal age-related complications from treatment’s after effects is difficult for the researchers, too — but not impossible. Several findings have come out of the Hutch’s LTFU Program, including the discovery in the early 1980s of chronic graft-vs.-host-disease. Lee now leads a national consortium headquartered at the Hutch dedicated to investigating new therapies for that devastating complication.

And there’s a reason that it can be hard to sift out late effects of transplantation from aging-related health problems: Martin and his colleagues found that transplantation, on average, takes about 10 years of biological age from survivors. Survivorship researcher Dr. Eric Chow has found that transplant survivors are at slightly higher risk for heart disease.

“As much as we’d like to restore people to their previous health, we can’t,” Martin said. Although there are lifestyle changes survivors can make to mitigate some of this damage, he said.

Ultimately, even if researchers don’t have solutions for all of transplantation’s or other therapies’ late effects, they need to know what they are, Martin said.

“I think it’s really important for people who design therapies to understand what the late effects are. If you don’t look, you won’t find it,” he said. “If we’re not looking and not finding them, we can’t tell people about them, and that’s something that could come back to haunt us in the long run. We have to be looking.”

Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel_Tompa.

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